Gram-negative bacteria that are resistant to aminoglycoside, β-lactam, and fluoroquinolone antibiotics are increasingly common. These bacteria are often only susceptible to the polymyxins and related peptides having antibacterial properties. As a result, there is renewed interest in the use of polymyxins for the treatment of multidrug-resistant gram-negative bacterial infections in humans.
Peptides such as polymyxin B and the related colistin (polymyxin E) have been administered to humans as antibacterial agents. However, their use has been previously limited because of their toxicity. These peptides comprise a seven amino acid cyclic peptide attached to an exocyclic three amino acid chain, wherein the N-terminal amine of the exocyclic chain is linked to a “side chain” or “tail”. The tail is an acyl group.
Renal toxicity has been observed with the recommended dosing of polymyxin B in some patients. Neurotoxicity or neuropathy has also been observed in patients with compromised renal functions, with an overall incidence of 7.3% reported in one large study with colistin (see, e.g., Evans, et al. (1999) Ann. Pharmacother. 33:960-967). When the acyl exocyclic chain and the adjacent N-terminal 2,4-diaminobutanoic acid (Dab) residue are enzymatically removed from polymyxin, this yields the corresponding polymyxin nonapeptide. The in vivo toxicity of the nonapeptide of polymyxin B is significantly less than that of polymyxin B itself (see, e.g., Kimura, et al. (1992) J. Antibiot., 45, 742-749). The toxicity of the nonapeptide in cell culture is reduced by about 100-fold relative to polymyxin B. However, the antibacterial activity of the nonapeptide is also reduced by about 2-64 fold relative to polymyxin B (see, e.g., Duwe, et al. (1986) Antimicrob. Agents Chemother, 30:340-341).
Attempts have been made to chemically modify polymyxin and colistin in order to obtain peptides with improved antibacterial properties and reduced toxicity. For example, the total synthesis of polymyxin B and four analogues was previously accomplished by a combination of solid phase peptide syntheses to obtain linear structures, followed by removal from the resin and condensation in solution at high dilution to obtain the cyclic peptide structure (see, e.g., Tsubery (2001) Peptides. 22: 1675-1681). The derivatives, however, were less active than polymyxin B. A more recent total synthesis of polymyxin B and a few closely related compounds was accomplished only by solid phase peptide synthesis (see, e.g., DeVisser, et al. (2003) J. Peptide Res. 61, 298-306 and Kline, et al. (2001) J. Pept. Res., 57: 175-187). Although both of these solid phase total synthetic approaches can provide new derivatives of polymyxin, these methods appear limited since the quantities of antibiotic produced are small and require large amounts of amino acid precursors. Any scale up of these methods for clinical studies may prove to be difficult and prohibitively costly. Further, neither of these methods is known to have produced novel derivatives of polymyxin having both improved antibacterial and toxicity properties relative to polymyxin B.
Thus, there is a need for new peptide compounds having equivalent antibacterial properties to polymyxin B, but with significantly lower toxicity, such as renal toxicity, as well as methods of manufacturing such antibacterial compounds.